The majority of head and neck squamous cell carcinoma (HNSCC) patients who recur present with unresectable disease for which current chemotherapy regimens result in only brief response in 10-30%, median survival of 5 to 6 month and few long term cures. Novel agents are therefore desperately needed to improve the outcome of these patients. Tumor angiogenesis, elevated interstitial fluid pressure, hypoxia, as well as overexpression of VEGF, PDGF, and VEGFR2 in HNSCC have all been found to correlate with aggressive disease, poor prognosis, and resistance to conventional therapy. Therefore, drugs with a broad spectrum of angiogenesis targets may induce a better clinical response in HNSCC patients than conventional chemotherapy by destroying the tumor microvasculature. AZD2171 (NSC732208) is an orally available small molecule receptor tyrosine kinase inhibitor with potent activities against VEGFR1, 2, and 3 as well as PDGFRB. In this study, we propose a phase II clinical trial of AZD2171 monotherapy in patients with unresectable recurrent HNSCC. Our primary objective is to assess the efficacy and safety of AZD2171 in this patient population. Our secondary objective is to correlate clinical response with indicators of therapeutic efficacy. The unique accessibility of many recurrent HNSCC allows biopsy and will enable us to validate these surrogate markers with morphological and physiological changes in the tumor. A better understanding of the biological effect of AZD2171 may facilitate further development of this novel agent in the treatment o head and neck cancer. We propose three specific aims: AIM 1: Determine the clinical response and toxicity profile of AZD2171 in recurrent head and neck cancer. AIM 2: Evaluate the early and late antiangiogenic effects of AZD2171 and identify potential surrogate markers of response AIM 3: Identify differentially expressed genes that correlate with HNSCC tumor response during AZD2171 therapy [unreadable] [unreadable] [unreadable]